The availability of (nearly) complete genome sequences for a few model organisms and for humans is expected to change the way we can formulate and address biological questions. With nearly complete sets of genes in hand, the traditional approach of studying one gene and/or one protein at-a-time can now be complemented by more global approaches that consider the proteins of a cell, a tissue or an organism, all at once. However most proteins predicted from genome sequences have not been characterized experimentally. Thus, an important challenge ahead is to develop functional genomics or proteomics strategies to accelerate the assignment of potential functions for large numbers of genes and proteins. A good model system to develop the concepts and technologies needed for functional genomics approaches is the nematode C. elegans. First because its genome is nearly completely sequenced but also because of its convenience for genetic studies and the availability of a complete cell fate map. Functional genomics is developing rapidly in C. elegans. A DNA microarray has been developed. Large-scale gene knock-out projects are underway. Systematic protein localization mapping projects have been initiated to define at what stage of development and in what cell each protein is expressed. In this context our long-term goal is to generate a comprehensive protein-protein interaction map for C. elegans. Three years ago, we decided to focus on the two-hybrid system as a first step. In our progress report we describe the results of semi-automated two-hybrid screens for 150 proteins and show that the method: i) is amenable to automation, ii) recovers approximately 50 percent of previously known interactions, and iii) provides functional annotation for large numbers of uncharacterized gene products. In addition we describe that, by July 1st 01, we should have Gateway-cloned most of the C. elegans protein-encoding full-length open reading frames (ORFs). Here we propose to generate version 1.0 of the C. elegans protein interaction map. First we will subclone most ORFs into the DNA-binding (DB) and activation domain (AD) plasmids of the two-hybrid system. Second, we will screen all pairwise combinations between the corresponding DB-X and AD-Y fusion proteins. Finally, since approximately 75,000 potential interactions are expected from this work, we will describe how we plan to deal with the challenge of using this information, making it publicly available, integrating it with other functional genomic databases, and last but not least interpreting it.